Cytomegalovirus (CMV) retinitis immune restoration disease occurs during highly active antiretroviral therapy-induced restoration of CMV-specific immune responses within a predominant Th2 cytokine environment

Plasma levels of cytomegalovirus (CMV)-specific immunoglobulin G (IgG), soluble (s) CD30, sCD26 (dipeptidyl peptidase IV [DPP IV]) enzyme activity, and tumor necrosis factor receptor-I (TNFR-I) were assessed in human immunodeficiency virus (HIV)-infected patients who experienced CMV retinitis (CMVR) as an immune restoration disease (IRD) during their first 6 months of highly active antiretroviral therapy (HAART) and in CMV-seropositive, HIV-infected patients with similar baseline CD4(+) T cell counts who had uneventful immune reconstitution. Patients who experienced CMVR IRD had a significant increase in CMV-specific IgG during their first 12 months of HAART, indicating restored CMV-specific immune responses. They also had significantly higher levels of sCD30 both before HAART and for up to 12 months after start of treatment. sCD30 levels remained elevated during 48 months of HAART, suggesting persistence of a predominant Th2 cytokine environment. Levels of sCD26 (DPP IV) enzyme activity and TNFR-I did not differ significantly between the 2 groups at any time point.     

Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART

Objectives We have previously described immune restoration diseases (IRD) associated with asymptomatic opportunistic infections presenting in immunodeficient HIV patients responding to highly active antiretroviral therapy (HAART). Here we address the question of whether patients with a history of IRD exhibit persistent immune activation, shown by elevated levels of interleukin‐(IL)‐6 and soluble IL‐6 receptor (sIL‐6R).
Methods Peripheral blood mononuclear cells (PBMCs) and plasma were collected from HIV patients with nadir CD4 T cell counts of < 80/µL and who had achieved immune reconstitution after HAART with ( n =14) or without ( n =15) experiencing IRD, severely immunodeficient (SID) patients with < 80 CD4 T cells/µL ( n =8) and HIV seronegative controls ( n =15). PBMC production and plasma levels of IL‐6, sIL‐6R and interferon (IFN)‐γ (PBMC only) were measured by enzyme linked immunosorbent assay (ELISA). Intracellular flow cytometry was used to determine the predominant cellular source of IL‐6 in HIV patients and controls.
Results Unstimulated PBMC from IRD patients produced significantly higher amounts of IL‐6 and sIL‐6R than non‐IRD patients and HIV seronegative controls. The sIL‐6R concentration was also significantly higher in supernatants from mitogen‐stimulated PBMC from IRD patients compared to non‐IRD patients. The production of IFN‐γ did not differ between IRD and non‐IRD patients. IRD patients had significantly higher plasma levels of IL‐6 compared to non‐IRD patients, SID patients and controls. Monocytes were the predominant source of IL‐6 in both HIV patients and controls.
Conclusions Patients with a history of IRD after HAART have elevated levels of IL‐6 and sIL‐6R.     

Short communication: decreasing soluble CD30 and increasing IFN-gamma plasma levels are indicators of effective highly active antiretroviral therapy

It was previously reported that without highly active antiretroviral therapy (HAART), secretion of Th1 cytokines and antiviral IFN-gamma in HIV-infected patients is decreased, whereas the production of Th2 cytokines, proinflammatory cytokines, and TNF-alpha is increased. We studied the effect of HAART on Th1-, Th2-, and monocyte-derived cytokines, and on the Th2-type immune response marker soluble (s)CD30 in HIV-1-infected hemophilia patients. Viral Load (VL), CD4+ lymphocyte counts, and plasma levels of sIL-1RA, IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-7, IL-10, TNF-alpha, TGF-beta2, IFN-gamma, and sCD30 were measured in 18 patients who received HAART. Nine patients were initially treatment-naive and were monitored after the initiation of HAART. sCD30 median levels were significantly higher in treatment-naive patients than in patients who were on HAART (77 vs. 30 U/ml, p = 0.005). A strong association was observed between sCD30 and VL (r = 0.85, p = 0.004). After the initiation of HAART, sCD30 levels decreased and remained low (at 1 year, 38; at 2 years, 41 U/ml; p = 0.012 and p = 0.021, respectively, as compared to baseline level) and this was accompanied by a decrease in VL and monocyte-derived IL-6 and an increase in CD4+ lymphocyte counts and Th1-derived IFN-gamma. One year after the initiation of HAART a strong inverse correlation was observed between IFN-gamma and VL (r = -0.83, p = 0.006). In contrast to sCD30 and IFN-gamma, CD4 counts and plasma IL-6 did not correlate with VL at any time. Our data suggest that decreasing sCD30 and increasing IFN-gamma plasma levels are indicators of effective HAART treatment and CD4 Th1 cell recovery in HIV-infected patients.     

Immune activation in patients infected with HIV type 1 and maintaining suppression of viral replication by highly active antiretroviral therapy

Immune activation associated with HIV infection declines after highly active antiretroviral therapy (HAART), but may persist or recur in some patients. It is not clear whether this reflects a resurgence of HIV replication or another cause of immune activation, such as inflammatory reactions to opportunistic pathogens (immune restoration disease [IRD]). Here, we studied plasma and cellular immune activation markers in adult HIV-1 patients who had received HAART for >12 months and maintained plasma HIV RNA levels of <400 copies/ml for >6 months. Plasma interleukin 1 receptor antagonist and tumor necrosis factor receptor I levels were similar in patients and HIV-negative control subjects, but the highest levels occurred mainly in patients with a history of IRD. In contrast, expression of HLA-DR and CD38 on monocytes and of HLA-DR on CD8(+) T cells was higher in patients than in control subjects. Thus, cellular markers of immune activation are abnormal in some patients with a good virological response to HAART, and abnormalities of plasma immune activation markers correlate with a history of IRD.     

Association of increased hepatitis C virus (HCV)-specific IgG and soluble CD26 dipeptidyl peptidase IV enzyme activity with hepatotoxicity after highly active antiretroviral therapy in human immunodeficiency virus-HCV-coinfected patients

Hepatotoxicity was investigated, using plasma collected before and during treatment, in 16 human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected patients who responded to highly active antiretroviral therapy (HAART), during a retrospective longitudinal study. Eleven patients experienced hepatotoxicity (i.e., a >3-fold increase in alanine aminotransferase level) while receiving HAART, including 4 patients with clinical hepatitis. Control subjects were 5 patients without hepatotoxicity. Markers of HCV-specific immune responses (HCV core-specific immunoglobulin G [IgG] antibody), T cell activation (soluble [s] CD26 dipeptidyl peptidase IV [DPP IV] enzyme activity), and inflammation (nitrate/nitrite and soluble tumor necrosis factor receptor I [sTNFRI] levels) were correlated with liver damage and immune reconstitution. All patients with hepatotoxicity had increased HCV core-specific IgG antibody and sCD26 (DPP IV) activity but did not have increased nitrate/nitrite or sTNFRI levels. Hepatotoxicity without clinical hepatitis was associated with increased CD8 T cell counts. Thus, hepatotoxicity in HIV-HCV-coinfected patients who respond to HAART is associated with increased HCV-specific immune responses and T cell activation.     

Immune restoration disease: a consequence of dysregulated immune responses after HAART

Immune Restoration Diseases (IRD) are a collection of atypical 'opportunistic infections' and inflammatory diseases seen in human immunodeficiency virus (HIV) patients after HIV viraemia is suppressed by highly active antiretroviral therapy (HAART). IRD probably reflect dysregulated immune responses against pre-existing infections by opportunistic pathogens, with different immunopathological mechanisms for different pathogens. For example, mycobacterial IRD are associated with delayed type hypersensitivity (DTH) responses to mycobacterial antigens, whereas patients who experience cytomegalovirus (CMV) IRD have elevated plasma levels of soluble CD30, a marker of a T2 cytokine environment expressed by activated CD8 T-cells. As IRD are often compartmentalised to organs, monitoring serological markers such as pathogen-specific IgG antibody, may be informative, as demonstrated for CMV and hepatitis C virus (HCV)-associated IRD. Genetic studies have provided evidence of distinct immunopathological mechanisms and inherited susceptibility to IRD associated with mycobacterial and herpesviridae infections. The expansion of HAART in the developing world where many HIV patients have low CD4+ T-cell counts and high rates of concomitant infections will place a large number of patients at-risk of developing IRD. It is therefore important to understand the immunopathology so that prevention, diagnosis and treatment can be improved.     

艾滋病的高效抗逆转录病毒治疗、疗效观察及其对免疫功能的影响

目的 为探讨艾滋病高效抗逆转录病毒治疗、疗效观察及其对免疫功能的影响.方法 应用HAART疗法对4例有严重免疫功能低下的HIV/AIDS病人进行治疗.结果 所有病人在治疗4周HIV复制被明显抑制,血浆病毒载量平均下降1.99log/ml(0.73～2.46log/ml),CD_8~ 、CD_4~ 细胞和血浆IL-2浓度在4～12周后持续性显著增高,上升幅度分别为67.2%,103.0%,255.1%,而血浆sIL-2R、IL-6、TNF-α、sTNFR-I、Neopterin浓度在治疗4～12周后持续下降至正常水平或以下.HAART治疗后各因素变化间的相关性分析显示,CD_4~ 细胞数与CD_8~ 、CD_3~ 细胞和血浆IL-2浓度之间,血浆病毒载量与sIL-2R、IL-6、TNF-α、sTNFR-I、Neopterin之间,sTNFR-I和Neopterin与sIL-2R、IL-6、TNF-α之间均存在明显正直线相关性;而CD_4~ 细胞数与血浆病毒载量、sIL-2R、sTNFR-I、Neopterin之间.以及IL-2和sIL-2R之间则有明显负直线相关性.结论 抗病毒治疗效果、病毒复制和免疫活化间具有密切关系,HAART治疗能快速有效地抑制HIV-1的复制,纠正机体免疫功能紊乱和重建免疫功能;外周血CD_4~ 细胞数、血浆病毒载量、IL-2、sIL-2R、TNF-α、sTNFR-I、Neopterin的浓度变化可以作为HAART治疗效果评价的重要指标.     

Soluble interleukin-6 receptor as a prognostic factor in multiple myeloma

Interleukin-6 (IL-6) is a major growth factor for the clonal malignant plasma cells in multiple myeloma (MM). The effect of IL-6 may be enhanced by soluble IL-6 receptor (sIL-6R). As there is a clinical need for improved stratification of MM patients at diagnosis, we have studied the role of sIL-6R as a prognostic marker in 207 newly diagnosed MM patients. Serum sIL-6R concentration was above the upper reference limit in 47% of the patients at diagnosis. The concentrations of sIL-6R and two other prognostic factors, IL-6 and β-2 microglobulin (β2M), were all significantly higher in the patients who died within 3 years compared with those who survived. However, serum sIL-6R did not show linear correlation with IL-6 or β2M levels. In univariate logistic regression analysis sIL-6R was a significant predictor of 3-year mortality. Kaplan-Meier analysis showed that raised levels of sIL-6R were associated with shorter survival. When the patients were stratified into four groups according to their serum IL-6 and sIL-6R levels, the patients with normal serum levels of both parameters had clear survival benefit. As β2M was the most powerful prognostic factor in the multivariate analysis, the patients were also stratified according to their serum β2M and sIL-6R levels. The patients with raised levels of both β2M and sIL-6R had shorter survival than the patients in the other three groups. Thus, measurement of these parameters at diagnosis would help to stratify MM patients.     

Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease

Interleukin-6 (IL-6) plays pathologic roles in immune-inflammatory diseases such as rheumatoid arthritis (RA) and Castleman disease. By inhibiting IL-6 receptors (IL-6Rs), tocilizumab (a humanized anti-IL-6R antibody) ameliorates the symptoms of these diseases and normalizes acute-phase proteins, including C-reactive protein (CRP). We found that tocilizumab treatment increased serum levels of IL-6 and soluble IL-6R (sIL-6R). To investigate the pathologic significance of these increases, we analyzed the kinetics of serum IL-6 and sIL-6R and the proportion of sIL-6R saturated with tocilizumab after tocilizumab administration in patients with RA and Castleman disease and then compared the results with the CRP values. Serum IL-6 and sIL-6R markedly increased after tocilizumab administration in both RA and Castleman disease. As long as free tocilizumab was detectable, sIL-6R was saturated with tocilizumab and IL-6 signaling was completely inhibited. We concluded that it is likely that sIL-6R increased because its elimination half-life was prolonged by the formation of tocilizumab/sIL-6R immune complex, and that free serum IL-6 increased because IL-6R-mediated consumption of IL-6 was inhibited by the unavailability of tocilizumab-free IL-6R. We also concluded that the increased level of free IL-6 during tocilizumab treatment closely reflects the actual endogenous IL-6 production and true disease activity.     

Soluble adhesion molecules and cytokines in patients with myasthenia gravis treated by plasma exchange

Plasma exchange (PE) is an effective therapeutic method used in patients with myasthenia gravis (MG) refractory to common therapy and/or with life-threatening respiratory complications. Except for acetylcholine receptor antibodies (AChRAbs), some other inflammatory mediators possibly activated in MG may also be removed during PE. Serum levels of soluble adhesion molecules (sICAM-1 and sVCAM-1), IL-6 and soluble receptors for IL-2 (sIL-2R), IL-6 (sIL-6R) and TNF alpha (sTNF-R II) were measured in 20 MG patients assigned to treatment with PE. On the basis of the serum levels of AChRAb the patients were subdivided into 2 groups (8 patients with low AChRAb, 12 patients with high AChRAb). Soluble adhesion molecules and cytokines were measured before the first and last PE, at the end of the first PE and in the samples of plasma filtrate obtained during the first PE. Before the first PE patients with MG had higher serum levels of sICAM-1, sVCAM-1, sIL-2R and sTNF-R II than controls. Both after the first PE and during the course of PE, a substantial decrease in serum levels of AChRAb, sICAM-1 and sVCAM-1 was recorded. However, serum levels of sIL-2R and sTNF-R II were not significantly influenced by either a single treatment or during the course of PE. There were high levels of AChRAb, soluble adhesion molecules and soluble cytokine receptors in plasma filtrates too. Patients with high circulating AChRAb had higher serum levels of sICAM-1 and sVCAM-1 than patients with low AChRAb. Increased serum levels of soluble adhesion molecules and soluble cytokine receptors in patients with MG suggest some systemic activation of the immune response which is more pronounced in patients with high circulating AChRAb. PE led to the decrease in serum AChRAb and soluble adhesion molecules due to their effective filtration but, on the other hand, serum levels of soluble cytokine receptors were not influenced by PE, in spite of their effective filtration which is probably counteracted by their increased production, possibly stimulated by the contact of the blood with the synthetic membrane.     

Comparison of serum IL-1β, sIL-2R,IL-6, and TNF-α levels with disease activity parameters in ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic, inflammatory, rheumatological disease affecting primarily the sacroiliac joint and vertebral column, with an etiology that remains obscure. Cytokines are soluble proteins that have specific roles in inflammatory response, arranging the interaction between cells of the immune system both in natural and specific immune reactions. This study was planned to evaluate the relation between the level of cytokines and the clinical and laboratory findings of patients with AS compared to healthy subjects. In this study, we demonstrated increased serum levels of soluble interleukin-2 receptor (sIL-2R), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in patients with AS compared with healthy subjects. Only IL-1β levels were not increased in AS patients. We found a correlation between C-reactive protein and IL-6 levels and between erythrocyte sedimentation rate and sIL-2R, IL-6 and TNF-α levels. Only the sIL-2R level was correlated with Bath AS Metrology Index and Bath AS Functional Index. We suggest that sIL-2R, IL-6, and TNF-α may have a role in the pathogenesis of AS and that their serum levels can be used as disease activity parameters and tools for diagnosis.     

Elevated serum levels of soluble immune activation markers are associated with increased risk for death in HAART-naive HIV-1-infected patients

The aim of this study was to determine the serum levels of soluble markers reflecting different aspects of immune activation in HIV-1-infected patients, and assess their prognostic significance for occurrence of AIDS-related death before the advent of the highly active antiretroviral treatment (HAART). Serum concentrations of the soluble forms of interleukin-2 receptors (sIL-2R), intercellular adhesion molecule-1 (sICAM-1), and E-selectin (sEs) have been determined in a cohort of 64 HIV-1-infected patients, between 1990-1993. The patients were followed prospectively with regular visits at the outpatient department. Follow-up time was censored at January 1, 1997, the date after which HAART was introduced. The median follow-up time was 46 months (range, 2-78 months). By the end of follow-up, 34 subjects had died. Baseline levels of all three soluble markers were significantly lower in subjects who remained alive during the follow-up compared to subjects who died. Univariate analysis showed that individual sIL-2R and sICAM-1, but not sEs measurements, were significantly associated with time to death (p = 0.008 and 0.003, respectively). Even after adjustment for age and CD4+ T-cell counts sIL-2R measurements remained significantly prognostic. Sensitivity analysis using follow-up time to year 2000 confirmed these results. Our data suggest that assessment of the immune activation status using the easily measured levels of circulating markers may provide additional information about the risk of AIDS-related death. Further studies are needed to assess the effect of HAART on the levels of immune activation markers and their prognostic value.     

Frequently relapsing Crohn's disease is characterized by persistent elevation in interleukin-6 and soluble interleukin-2 receptor serum levels during remission

We examined immune and inflammatory activation during remission in patients with Crohn's disease who presented with various clinical profiles (prolonged remission vs. relapsing disease). Thirty-six patients with at least 3 years' follow-up starting from a remission period were studied retrospectively. Relapses were defined by a retrospective calculation of the Crohn's disease activity index or by the clinical judgement of the physicians in charge of the patients. Disease course over the study period was assessed by the mean number of annual relapses. Analysis used measurements during remission of the following: erythrocytes sedimentation rate, relative lymphocytosis, acid alpha1-glycoprotein, interleukin-6 (IL-6), and soluble interleukin-2 receptor (sIL-2R) serum levels. During the study period 21 patients experienced at least one relapse and 15 did not. Mean serum levels of sIL-2R and mean relative lymphocytosis in remission significantly discriminated between relapsing and nonrelapsing patients. Only the mean sIL-2R serum level was selected by multivariate analysis, with a cutoff value of 82 pM/1 (sensitivity of 76% and specificity of 80%). The only features correlated with mean number of annual relapses in the relapsing patients were mean serum levels of sIL-2R (r=0.58, P=0.015) and IL-6 in remission (r=0.45, P=0.039). Multivariate analysis demonstrated statistical significance only for the mean serum level of IL-6 (P=0.014). In Crohn's disease the persistent elevation in sIL-2R serum levels during remission corresponds to chronic active disease, while high serum levels of IL-6 in these patients is associated with a high frequency of relapse.     

Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6.

It has been reported that soluble interleukin (IL)-6 receptor (sIL-6R) is detected in the serum of healthy individuals and its level is increased in patients with multiple myeloma and human immunodeficiency virus infection. Although several reports have suggested that sIL-6R potentiates IL-6 action, its physiological role remains unclear. In this study, we examined the role of sIL-6R on osteoclast formation by IL-6, using a coculture of mouse osteoblasts and bone marrow cells. Neither recombinant mouse IL-6 (mIL-6) nor mouse sIL-6R (smIL-6R) induced osteoclast-like multinucleated cell (MNC) formation when they were added separately. In contrast, simultaneous treatment with mIL-6 and smIL-6R strikingly induced MNC formation. These MNCs satisfied major criteria of authentic osteoclasts, such as tartrate-resistant acid phosphatase (TRAP) activity, calcitonin receptors, and pit formation on dentine slices. The MNC formation induced by mIL-6 and smIL-6R was dose-dependently inhibited by adding monoclonal anti-mouse IL-6R antibody (MR16-1). It is likely that osteoblasts and osteoclast progenitors are capable of transducing a signal from a complex of IL-6 and sIL-6R through gp130, even though they may have no or a very small number of IL-6Rs. Factors such as IL-11, oncostatin M, and leukemia inhibitory factor, which are known to exert their functions through gp130 (the signal-transducing chain of IL-6R), also induced MNC formation in our coculture system. These results suggest that increased circulating or locally produced sIL-6R induces osteoclast formation in the presence of IL-6 mediated by a mechanism involving gp130. This may play an important physiological or pathological role in conditions associated with increased osteoclastic bone resorption.     

Involvement of circulating interleukin-6 and its receptor in the development of euthyroid sick syndrome in patients with acute myocardial infarction

OBJECTIVE: In patients with acute myocardial infarction (AMI), low triiodothyronine (T(3)) levels with normal or subnormal levels of thyrotropin (TSH), the euthyroid sick syndrome (ESS), have been reported, however, the mechanism of altered thyroid hormone metabolism is unknown. Recent reports have shown that interleukin-6 (IL-6) plays a key role in the pathogenesis of AMI and ESS. This preliminary study investigates the relationship between thyroid states and plasma levels of IL-6, the soluble IL-6 receptor (sIL-6R), and the soluble transducing 130kDa glycoprotein (sgp130) in AMI. DESIGN AND METHODS: We measured the concentration of TSH, free T(3) (FT(3)), free thyroxine (FT(4)), IL-6, sIL-6R and sgp130 in plasma from 24 patients with AMI and 20 normal controls. RESULTS: All 24 AMI patients showed significantly lower concentrations of FT(3) with normal or subnormal levels of TSH, and higher concentrations of IL-6 and sIL-6R than controls. IL-6 level was correlated with creatine phosphokinase (CPK) and FT(3) levels but not with FT(4 )or TSH levels in patients with AMI. The time course of IL-6 and FT(3 )concentration seemed to be closely linked. sIL-6R level was correlated with CPK and sgp130 levels, but not with FT(3), FT(4) or TSH levels. FT(4 )level was correlated with sgp130 level. CONCLUSION: Patients with AMI develop ESS through activation of IL-6 and its receptor system.     

Enhanced production of interleukin-6 (IL-6), oncostatin M and soluble IL-6 receptor by cultured peripheral blood mononuclear cells from patients with systemic sclerosis.

OBJECTIVES: To determine whether the spontaneous production of interleukin 6 (IL-6), oncostatin M (OSM), soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130) from peripheral blood mononuclear cells (PBMC) is increased in patients with systemic sclerosis (SSc). METHODS: The culture supernatants of PBMC from patients with SSc (n = 33) and healthy controls (n = 20) were examined by enzyme-linked immunosorbent assay. RESULTS: The production levels of IL-6, OSM and sIL-6R were significantly higher in patients with SSc than in controls. However, sgp130 levels in supernatants from patients with SSc were not significantly elevated when compared with those from controls. Soluble IL-6R levels correlated significantly with the severity of pulmonary fibrosis in patients with SSc. CONCLUSIONS: The enhanced production of IL-6, OSM and sIL-6R from PBMC may cooperatively contribute to the disease process in SSc. In particular, enhanced sIL-6R production from PBMC may be related to the development of pulmonary fibrosis via enhancement of IL-6 signal transduction in SSc, since sIL-6R can act as an agonist of IL-6.     

Elevated serum levels of soluble interleukin-2 receptor in patients with Wegener's granulomatosis. Association with disease activity.

OBJECTIVE. To investigate whether soluble interleukin-2 receptor (sIL-2R), a marker of T cell activation, could be a useful marker of disease activity in Wegener's granulomatosis (WG). METHODS. Soluble IL-2R levels were determined by enzyme-linked immunosorbent assay. WG disease activity in 102 patients was assessed according to clinical features and levels of classic antineutrophil cytoplasmic antibody (c-ANCA) and C-reactive protein (CRP). RESULTS. Soluble IL-2R levels were higher in patients with generalized and active disease than in those with limited and inactive disease. In 25 patients with complete clinical remission, sIL-2R levels were significantly elevated, although levels of CRP and c-ANCA were normal. Eight of these 25 patients had disease relapses within 6 months. Levels of sIL-2R were significantly higher in patients who had relapses than in those who did not. Patients with clinically active WG but low c-ANCA or CRP levels had elevated levels of sIL-2R. CONCLUSION. Levels of sIL-2R correlate with disease activity in patients with WG, and may indicate imminent relapse.     

In subjects with antibody to hepatitis C virus a high serum level of interleukin-2 soluble receptor suggests activity of liver disease

The hepatitis C virus (HCV) is an RNA virus without apparent cytopathic effects, and hepatocellular damage in chronic infection is generally believed to be immune-mediated by cytotoxic T lymphocytes. Activated T cells release the soluble form of the interleukin-2 (IL-2) receptor (sIL-2R) and its concentration is correlated with the degree of lymphocyte activation. We measured sIL-2R in 69 subjects: 24 healthy repeat blood donors (group I), 17 HCV carriers without liver damage (group II) and 28 patients with HCV-related chronic active hepatitis (group III). There was no significant difference between sIL-2R levels in patients of group I (36.5±14.6Uml^–1) and group II (46.8±17.4Uml^–1), and the levels for both of these groups were significantly lower than those observed in the patients with active HCV, group III (176.9±59.5Uml^–1). Hence, among HCV-infected subjects (HCV RNA positive) with persistently normal alanine aminotransferase (ALT) levels, the plasma levels of sIL-2R are normal, but, in patients (HCV RNA positive) with HCV-related chronic active hepatitis there are increased plasma levels of sIL-2R. We conclude that in HCV infection high levels of sIL-2R are related to activity of the disease rather than to virus replication. In patients with HCV-related chronic liver disease, the sIL-2R concentration may be a useful marker of disease activity.     

Synovial fluid and serum levels of soluble interleukin-6 receptor in patients with rheumatoid arthritis

Our objective was to measure both synovial fluid (SF) and serum levels of soluble interleukin-6 receptor (sIL-6R) in patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA), and to investigate the amounts of sIL-6R protein produced by cultured synovial cells, chondrocytes and mononuclear cells (MNCs). We measured levels of sIL-6R using a sensitive and specific enzyme-linked immunosorbent assay. Synovial cells, chondrocytes and MNCs were cultured, and the supernatants were also measured for sIL-6R. SF levels of sIL-6R in RA were significantly higher than those in OA. SF levels of sIL-6R significantly correlated with SF levels of IL-6 in RA. The serum level of sIL-6R was approximately 3-fold higher than the SF level of sIL-6R. sIL-6R protein was not detected in the supernatants of synovial cells and chondrocytes. As compared to the SF levels of sIL-6R, a small amount of sIL-6R protein was produced by SF MNCs. The above findings suggest that increased amounts of sIL-6R form IL-6-sIL-6R complexes which mediate IL-6 function in RA joints and that SF sIL-6R protein might be not only produced in affected joints, but also supplied from the serum.